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Purity: ≥98%
Fesoterodine Fumarate (SPM907; Toviaz, SPM-907), the fumarate salt of Fesoterodine which is a prodrug of 5-hydroxymethyl tolterodine, is a muscarinic AChR receptor antagonist that has been approved for treating overactive bladder syndrome.
| Targets |
M1 muscarinic receptor (Ki = 3.6 nM) [3]
- M2 muscarinic receptor (Ki = 4.4 nM) [3] - M3 muscarinic receptor (Ki = 1.8 nM) [3] - M4 muscarinic receptor (Ki = 2.7 nM) [3] - M5 muscarinic receptor (Ki = 5.1 nM) [3] |
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| ln Vitro |
Fesoterodine fumarate raises the volume expelled with each micturition while reducing the frequency, intensity, and urgency of incontinence episodes[1]. Following oral administration, nonspecific esterases quickly and completely hydrolyze fesoterodine fumarate in plasma to produce desfesoterodine, an active metabolite of fesoterodine (5-hydroxymethyl tolterodine; SPM 7605 ; HY-76569)[3][4].
Fesoterodine Fumarate (1-100 nM) competitively bound to human recombinant M1-M5 muscarinic receptors, with highest affinity for M3 subtypes (Ki = 1.8 nM) [3] - Incubation of isolated human bladder smooth muscle cells with Fesoterodine Fumarate (0.1-10 μM) dose-dependently inhibited acetylcholine-induced contraction, with IC50 of 2.3 μM and maximum inhibition (88%) at 10 μM, mediated via M3 receptor antagonism [3] - The active metabolite of Fesoterodine Fumarate (5-hydroxymethyl tolterodine, 5-HMT) showed comparable muscarinic receptor affinity (Ki 1.5-4.8 nM) and contractile inhibition (IC50 = 2.1 μM) to the parent drug [3,4] - Fesoterodine Fumarate (10 μM) had no significant effect on human neuronal sodium channels or potassium channels, indicating minimal central nervous system off-target activity [4] |
| ln Vivo |
At the lowest studied dose of 0.01 mg/kg, fesoterodine fumarate (0.01-1 mg/kg; IV) decreases micturition pressure, increases bladder capacity, and increases ICIs (intercontraction intervas)[3].
Oral administration of Fesoterodine Fumarate (0.1-1 mg/kg/day) to rats with cyclophosphamide-induced overactive bladder for 7 days reduced micturition frequency by 42% and increased voided volume per micturition by 38%, with maximum efficacy at 0.5 mg/kg/day [3] - In streptozotocin-induced diabetic rats with erectile dysfunction, Fesoterodine Fumarate (0.3 mg/kg/day, po) for 28 days improved erectile function, increasing intracavernosal pressure (ICP) by 55% and restoring ICP/mean arterial pressure (MAP) ratio by 40% [2] - In healthy volunteers, oral Fesoterodine Fumarate (4 mg/day) for 14 days reduced 24-hour urinary frequency by 27% and urgency episodes by 32%, consistent with clinical efficacy in overactive bladder [1,4] |
| Enzyme Assay |
Muscarinic receptor binding assay: Membrane fractions from HEK293 cells expressing human M1-M5 receptors were prepared. Fesoterodine Fumarate (0.001-100 nM) was incubated with membranes and [³H]N-methylscopolamine at 25°C for 60 minutes. Unbound ligand was removed by filtration, and bound radioactivity was quantified. Ki values were calculated via competitive binding analysis [3]
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| Cell Assay |
Bladder smooth muscle contraction assay: Isolated human bladder smooth muscle cells were seeded in 24-well plates and cultured to confluence. Cells were precontracted with acetylcholine (1 μM), then treated with Fesoterodine Fumarate (0.1-10 μM) for 60 minutes. Cell contraction was assessed by measuring changes in cell surface area via image analysis [3]
- Neuronal channel activity assay: Human cortical neurons were cultured for 14 days. Fesoterodine Fumarate (1-50 μM) was added to the medium, and sodium/potassium channel currents were recorded using whole-cell patch-clamp technique to evaluate off-target effects [4] |
| Animal Protocol |
Animal/Disease Models: Bladders from female SD (Sprague-Dawley) rats (225-275 g)[3]
Doses: 0.01, 0.1 and 1 mg/kg Route of Administration: IV Experimental Results: decreased the micturition pressure and increased bladder capacity and ICIs at the lowest dose tested of 0.01 mg/kg. Bladder smooth muscle contraction assay: Isolated human bladder smooth muscle cells were seeded in 24-well plates and cultured to confluence. Cells were precontracted with acetylcholine (1 μM), then treated with Fesoterodine Fumarate (0.1-10 μM) for 60 minutes. Cell contraction was assessed by measuring changes in cell surface area via image analysis [3] - Neuronal channel activity assay: Human cortical neurons were cultured for 14 days. Fesoterodine Fumarate (1-50 μM) was added to the medium, and sodium/potassium channel currents were recorded using whole-cell patch-clamp technique to evaluate off-target effects [4] |
| ADME/Pharmacokinetics |
Fexolodine fumarate is a prodrug that is rapidly absorbed after oral administration, with an oral bioavailability of 52% in humans [1,4]. It is metabolized in the liver by cytochrome P450 3A4 (CYP3A4) and CYP2D6 to the active metabolite 5-hydroxymethyltolterodine (5-HMT), which mediates most of the therapeutic effects [1,3]. The elimination half-life (t1/2) of 5-HMT in humans is 7–9 hours, supporting once-daily oral administration [1,4]. Approximately 70% of the administered dose is excreted in the urine within 24 hours (10% as the parent drug and 60% as 5-HMT and its metabolites) [4]. It has a wide tissue distribution, with the highest concentrations found in the bladder, kidneys, and liver [3].
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| Toxicity/Toxicokinetics |
When used clinically to treat overactive bladder, fexordine fumarate (4–8 mg/day, orally) causes mild anticholinergic adverse reactions, including dry mouth (28%), constipation (12%), and blurred vision (6%); no serious hepatotoxicity or nephrotoxicity has been reported [1,4]. - The plasma protein binding rates of fexordine fumarate and its metabolite 5-hydroxymethyltransferase (5-HMT) in human plasma are 92% and 95%, respectively [3]. - The acute oral LD50 of fexordine fumarate is 280 mg/kg in mice and 350 mg/kg in rats [3]. - At therapeutic doses, no significant drug interactions with CYP3A4 or CYP2D6 substrates/inhibitors have been observed [4].
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| References |
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| Additional Infomation |
Fesoterodine fumarate is the fumarate form of fexolodine, a competitive muscarinic receptor antagonist with muscle relaxant and urinary tract antispasmodic effects. Fexolodine is rapidly hydrolyzed in the body to its active metabolite, 5-hydroxymethyltolterodine, which binds to and inhibits the activity of muscarinic receptors on the detrusor muscle of the bladder, thereby preventing acetylcholine-induced bladder contractions or spasms. This results in relaxation of the bladder smooth muscle, increased bladder capacity, and reduced involuntary muscle contractions and involuntary leakage of urine. The active metabolite does not interact with α-adrenergic receptors, serotonergic receptors, histamine receptors, or excitatory amino acid receptors and is eliminated by renal excretion.
See also: Fexolodine (containing the active ingredient). Indications Treatment of symptoms that may occur in patients with overactive bladder (urinary frequency and/or urgency and/or urge incontinence). Fexordine fumarate is a prodrug and a competitive muscarinic receptor antagonist with the highest affinity for the M3 receptor (a key mediator of bladder smooth muscle contraction) [3,4]. - Its clinically approved indication is overactive bladder, which improves symptoms (frequency, urgency, urge incontinence, nocturia) by blocking the M3 receptor in the bladder [1,4]. - Its prodrug design ensures stable absorption and conversion to the active metabolite 5-HMT, which has similar efficacy to tolterodine but better pharmacokinetic properties [3,4]. - In addition to treating overactive bladder, fexordine fumarate has also shown potential benefit for erectile dysfunction in a diabetic rat model, suggesting additional therapeutic uses [2]. |
| Molecular Formula |
C26H37NO3.C4H4O4
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| Molecular Weight |
527.65
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| Exact Mass |
527.288
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| CAS # |
286930-03-8
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| Related CAS # |
Fesoterodine;286930-02-7;Fesoterodine-d7 fumarate;2747918-94-9
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| PubChem CID |
9849808
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| Appearance |
White to off-white solid powder
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| Boiling Point |
518.9ºC at 760 mmHg
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| Melting Point |
72-78ºC
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| Flash Point |
267.6ºC
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| LogP |
5.092
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
13
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| Heavy Atom Count |
38
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| Complexity |
610
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC(C)C(=O)OC1=C(C=C(C=C1)CO)[C@H](CCN(C(C)C)C(C)C)C2=CC=CC=C2.C(=C/C(=O)O)\C(=O)O
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| InChi Key |
MWHXMIASLKXGBU-RNCYCKTQSA-N
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| InChi Code |
InChI=1S/C26H37NO3.C4H4O4/c1-18(2)26(29)30-25-13-12-21(17-28)16-24(25)23(22-10-8-7-9-11-22)14-15-27(19(3)4)20(5)6;5-3(6)1-2-4(7)8/h7-13,16,18-20,23,28H,14-15,17H2,1-6H3;1-2H,(H,5,6)(H,7,8)/b;2-1+/t23-;/m1./s1
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| Chemical Name |
(E)-but-2-enedioic acid;[2-[(1R)-3-[di(propan-2-yl)amino]-1-phenylpropyl]-4-(hydroxymethyl)phenyl] 2-methylpropanoate
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.74 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.74 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.74 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 100 mg/mL (189.52 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8952 mL | 9.4760 mL | 18.9520 mL | |
| 5 mM | 0.3790 mL | 1.8952 mL | 3.7904 mL | |
| 10 mM | 0.1895 mL | 0.9476 mL | 1.8952 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Clinical Trial to Evaluate the Efficacy and Safety of Fesoterodine in Comparison to Tolterodine for Overactive Bladder (OAB)
CTID: NCT00444925
Phase: Phase 3 Status: Completed
Date: 2015-03-24
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